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• W4387332677 abstract "Tom McHugh studies the circuit mechanisms of memory in mice at the RIKEN Center for Brain Science in Japan. In an interview with Neuron, he talks about early influences at MIT, the joy of listening to place cells in a converted closet, and personal and scientific adjustments he’s made since coming to Japan. Tom McHugh studies the circuit mechanisms of memory in mice at the RIKEN Center for Brain Science in Japan. In an interview with Neuron, he talks about early influences at MIT, the joy of listening to place cells in a converted closet, and personal and scientific adjustments he’s made since coming to Japan. Thomas (Tom) McHugh is the team leader of the Laboratory for Circuit and Behavioral Physiology at the RIKEN Center for Brain Science in Wako-shi, Japan. He studied molecular and cell biology at the University of California, Berkeley, and then completed a PhD in the Department of Biology at the Massachusetts Institute of Technology (MIT). At MIT, he conducted his thesis work studying the genetics and physiology of spatial memory with Dr. Matt Wilson and Dr. Susumu Tonegawa. As a postdoc, he stayed on at MIT, working with Dr. Tonegawa to interrogate circuit mechanisms of hippocampal memory. In 2009, he moved to Japan to start his laboratory at the RIKEN Brain Science Institute. For the last 14 years, his group has taken a multidisciplinary approach to studying memory in the mouse, combining genetic tools and the field’s deep understanding of hippocampal physiology to investigate how memories are formed, stored, and recalled in the mammalian brain and how damage from factors like stress and disease impair these functions. He was the recipient of the Japan Brain Science Foundation’s Tsukahara award in 2019 and currently serves as the editor in chief of Neuroscience Research, the official journal of the Japan Neuroscience Society, and as a member of the Society for Neuroscience Public Education and Communication Committee. Like many of us, my initial interest in biology, and more specifically genetics, was based on my own family circumstances. I am the youngest of 9 children, and despite what the statistics predict, my oldest sibling, my brother Pat, who was 21 when I came along, was born with Down syndrome (DS). Despite our age gap, we were extremely close, and growing up I was always fascinated with how his genetic condition shaped him, in terms of both his limitations and achievements. This was my motivation to understand genetics and how genes connect to phenotypes, and my intention until early in graduate school was to focus my research on human genetics. While that plan changed, it was a special experience a few years ago when, via collaboration, my group published a study on the changes in hippocampal physiology in a DS mouse model, a bit of a full-circle moment. I was extremely fortunate as a young graduate student to stumble into the genesis of what was at the time called the Center for Learning and Memory, the precursor to the Picower Institute, at MIT. Susumu Tonegawa had just made his first two hires, Matt Wilson and Earl Miller, and their labs started as neighbors. My interest in genetics is what spurred me to join Susumu’s group, as this was soon after his group published the first set of knockout mouse learning and memory papers, but what led me to in vivo physiology was a combination of great timing and enthusiasm borne out of ignorance. Susumu was looking for someone from his lab to adapt Matt’s tetrode recordings to the mouse hippocampus. Despite zero knowledge of either electrophysiology or systems neuroscience, I agreed—and I still remember Susumu’s pitch “Do you like computers? Matt has a lot of computers in his lab!” This hasty decision turned into a career. Working in Matt’s lab and the daily discussions with Matt, Earl, and the fantastic trainees in both groups was where I learned neuroscience, and those experiences still shape my thinking to this day. It’s been interesting over the last 25 years to see the gaps between these fields close at an accelerating pace. As an undergrad, I studied molecular biology and started grad school with all intentions of continuing that path. At that time, there were very few labs that had the expertise to combine genetic approaches with in vivo activity monitoring, so when I began working with Susumu and Matt, we had a unique niche to explore and many exciting questions to ask. That contrasts with where we stand today, with the majority of systems neuroscientists employing genetic tools, even in non-human primates, and molecular neurobiologists translating their discoveries to systems-level questions. The barriers that separated disciplines have broken down, and the toolkits available have drastically expanded, making it much more difficult to label individuals as simply molecular or systems neuroscientists. I think this progress has been great for the field, and I enjoy recruiting people with varied backgrounds into my group to take advantage of the current approaches with their own unique perspectives. My favorite experiment is still the one that has been a constant throughout my career—recording from the hippocampus of the mouse as it runs around the environment. I still remember sitting in what was a converted closet in 1995 listening to the spiking of a single CA1 pyramidal cell for the first time and writing in my notebook “Mice have place cells!” In my group, I try to ensure all the trainees learn hippocampal in vivo recording and still enjoy the look on their faces when they record their own “first” place cell, an informal rite of passage in the lab. Of course, the field now agrees the hippocampus can encode much more than the current location of the animal, but I still think the accessibility and simplicity of those place responses are beautiful. With an admitted bias as a lifelong memory researcher, I think a mechanistic understanding of how memories are formed, stored, and recalled is a key question for both basic science and any rational design of approaches to treat memory-related disease. Over the course of my career, there has been tremendous progress on every level, from tools to analysis, that have brought us closer to an understanding, but clearly, we still have a long way to go. Personally, I often think about the moment when the encoding of an experience “begins,” as this is when the different mnemonic process converge—the recall of similar experiences, the comparison of those previous memories with current sensory and internal state information, the detection of novelty and the subsequent changes in plasticity, the triggering of behavioral programs that lead to memory encoding and/or updating—a suite of interconnected circuits and processes engaged simultaneously. I would be happy to have any understanding of how the circuits in the brain behave at that precise moment. I admire my colleagues and friends that constantly generate novel ideas to test, but I readily admit to my trainees that that is not my forte. Rather, I see our approach to be more like mechanics disassembling and reassembling an engine; I want to know how circuits in the brain work to support mnemonic function and enjoy making changes, putting everything back together and seeing what happens. Our strength still lies at the intersection of genetic approaches and the recording, either physiologically or, more recently, optically, of neuronal activity. When I was a grad student, I would tease my friends that the seminal discoveries they were making recording from rat hippocampus—replay, theta sequences, cross-region coupling—were giving me a roadmap for my future experiments, in which I could use genetic approaches to tease apart the underlying circuits and mechanisms that generate this structured activity. Many years later, things haven’t changed all that much. First, I encourage them to ask questions they are sincerely interested in. In science, if you are talented and lucky, pursuing a career as a researcher can lead to independence in one’s mid to late 30s. Compared to other jobs, it takes longer to become a leader and can be a more competitive and difficult path to follow. So, my advice, which is not pessimistic but rather realistic, is that you should ask yourself, “Do I really want to do this?” And if you don’t, that’s okay. When I look at the students who come to the lab, they are all very intelligent and motivated. I think these smart, young people can find many jobs that pay well, give them freedom, and provide a life that can be equally or even more rewarding than trying to be the principal investigator of a laboratory. I don’t think it’s necessary to view choosing that option as a setback. Life can be seen as a process of filling the various boxes inside you with satisfaction and happiness, and if you are lucky enough to find a path that allows you to pursue that, go for it. Scientifically I encourage them to not worry too much about competition—if someone else is working on it, then it’s probably interesting. Present your findings early and often and get and digest feedback; being first is nice, but being correct is most important. The one that sticks out in my own group was our project looking at the impact of chronic silencing of CA2 pyramidal cell transmission on hippocampal physiology. Given that we had previously seen clear but subtle phenotypes with similar manipulations in the dentate gyrus and CA3, I fully expected to find changes only after careful analysis of the data when we targeted the relatively small region of CA2. You can imagine my surprise when the technician doing the recordings rushed down to get me, saying “You have to see this!” What he observed, and was later published in Neuron (Boehringer et al., 2017), was that in mice running along a track in the absence of CA2 transmission, the entire dorsal hippocampus exhibited spatially triggered high-frequency population discharges that looked almost seizure-like in appearance—what we called in the lab “pleizures” for place seizures. These events had all the properties of single place cells: context specificity, spatial stability, directionality. It was a lot of fun working with the group and our collaborators to figure out a plausible mechanism for that dramatic phenotype. My family keeps me quite busy; my wife and I have a 16-year-old and a 12-year-old, so a typical day is pretty full between work and home. Living in Japan, I do enjoy the food and culture when we find time—in Tokyo, a great meal is typically just a few steps away. I still passionately follow sports in the US, particularly football and baseball. People in my lab know that virtually any morning during baseball season, there will be a game playing on one of the monitors in my office—a benefit of the time difference between the US and Japan is the 8 a.m. start times. I also enjoy road biking; I commute daily to the lab by bike and try to get out on the weekends for longer rides around Tokyo or in nearby prefectures where there is quite beautiful nature and an abundance of great riding. I often joke that moving from undergrad at Cal to my PhD at MIT was a bigger culture shock than my later move to Japan. As a child of working-class immigrants, my folks were born in rural Ireland and moved to the US in the late 1940s; my friends and peers at Berkeley were mostly students from similar circumstances, albeit their parents predominantly hailed from Asia, Mexico, or Central America. At MIT, however, I walked into a graduate student cohort that was quite different—many in my class came from families with academic or medical backgrounds, and they already knew the rules, both written and unwritten, of professional science. I was naive and a bit surprised, and it took quite some time to adjust to that world. That being said, of course it was a big adjustment moving to Japan, where neuroscience is a much smaller community than in the US and one in which connections are forged over many years. Integration, both personally and scientifically, took time and patience, but I am quite happy at how it has turned out. It’s exciting to see the community of international researchers based in Japan continue to grow and the connections between Japan and other countries in the region—China, Korea, Singapore, Australasia— strengthen in terms of scientific collaboration and cooperation. There has been a strong effort the last 5 years or so to create a FENS-type organization in Asia, and I am very much in favor of that. The honest answer is almost nothing keeps me awake at night; however, on the rare occasion it happens, it is usually questions of doubt rather than questions of inspiration. Am I handling a situation in lab or on a project in the best way? Did we miss something in our last analysis? Is a trainee struggling, and what can I do to help? Perhaps stereotypically, actual insights usually come when I least expect them, riding along the river on my bike, walking the dog, or watching a ball game. The older I get, the greater the need I find a way to quickly write them down before I forget! The author declares no competing interests." @default.
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